Process for making bivalirudin

Abstract

The present invention relates to the efficient commercial synthesis of Bivalirudin.

1. A process for the preparation of Bivalirudin comprising the steps of:
 a) condensing the segment AspPheGlu(tBu)Glu(tBu)IleProOBn (SEQ ID NO: 5) (S3) and the segment FmocGlyGlyGlyGlyAsnGlyOH (SEQ ID NO: 2) (S2) in a first organic solvent; 
 b) deprotecting the product of step a); 
 c) condensing the product of step b) and the segment Boc-D-PheProArg(HCl)ProOH (S1) in a second organic solvent; 
 d) deprotecting the benzyl group of the product of step c); 
 e) condensing the product of step d) and the segment Glu(tBu)Glu(tBu)Tyr(tBu)LeuOtBu (SEQ ID NO: 6) (S4) in a third organic solvent; and 
 f) deprotecting the product of step e) to obtain Bivalirudin. 
 
     
     
       2. The process according to  claim 1 , wherein the first, second and third organic solvents are independently selected from DCM, DMF, and DMSO. 
     
     
       3. The process according to  claim 1 , wherein the deprotection of the product of step b) is performed by using a nucleophilic base. 
     
     
       4. The process according to  claim 1 , wherein the deprotection of the product of step d) is performed by hydrogenation in presence of a catalyst. 
     
     
       5. The process according to  claim 1 , wherein the deprotection of the product of step f) is performed by reacting with a mixture of TFA/TIS/H 2 O to obtain Bivalirudin. 
     
     
       6. A process for the preparation of Bivalirudin comprising the steps of:
 a) condensing the segment AspPheGlu(tBu)Glu(tBu)IleProOBn (SEQ ID NO: 5) (S3) and the segment FmocGlyGlyGlyGlyAsnGlyOH (SEQ ID NO: 2) (S2) in a first organic solvent; 
 b) deprotecting the product of step a); 
 c) condensing the product of step b) and the segment Boc-D-PheProArg(HCl)ProOH (S1) in a second organic solvent; 
 d) deprotecting the benzyl group of the product of step c); 
 e) condensing the product of step d) and the segment Glu(tBu)Glu(tBu)Tyr(tBu)LeuOtBu (SEQ ID NO: 6) (S4) in a third organic solvent; and 
 f) deprotecting the product of step e) to obtain Bivalirudin; 
 wherein the first, second and third organic solvents are independently selected from DCM, DMF, and DMSO; the deprotection of the product of step f) is performed by reacting with a mixture of TFA/TIS/H 2 O to obtain Bivalirudin. 
 
     
     
       7. The process according to  claim 1 , wherein the deprotection of the product of step d) is performed by hydrogenation in the presence of a catalyst.